Small-molecule and Mutational Analysis of Allosteric Eg5 Inhibition by Monastrol

Overview

Journal BMC Chem Biol

Publisher Biomed Central

Specialty Biochemistry

Date 2006 Mar 1

PMID 16504166

Citations 33

Authors

Zoltan Maliga

Timothy J Mitchison

Affiliations

Soon will be listed here.

Abstract

Background: A recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel, induced-fit drug binding site at atomic resolution. Mutational obliteration of the monastrol binding site results in a monastrol-resistant, but otherwise catalytically active Eg5 motor domain. However, considering the conformational changes at this site, it is unclear what specific interactions stabilize the interaction between monastrol and the Eg5 motor domain.

Results: To study the molecular complementarity of the monastrol-Eg5 interaction, we used a combination of synthetic chemistry and targeted mutations in Eg5 to measure the contribution of specific contacts to inhibition of Eg5 in vitro and in cultured cells. Structure-activity data on chemical derivatives, sequence analysis of Eg5 homologs from different species, and the effect of mutations near the drug binding site were consistent with the crystal structure.

Conclusion: The mechanism of monastrol revealed by our data rationalizes its specificity for Eg5 over other kinesins and highlights a potential mechanism of drug resistance for anti-cancer therapy targeting this site in Eg5.

Citing Articles

Noncanonical interaction with microtubules via the N-terminal nonmotor domain is critical for the functions of a bidirectional kinesin.

Singh S, Siegler N, Pandey H, Yanir N, Popov M, Goldstein-Levitin A Sci Adv. 2024; 10(6):eadi1367.

PMID: 38324691 PMC: 10849588. DOI: 10.1126/sciadv.adi1367.

Drug resistance dependent on allostery: A P-loop rigor Eg5 mutant exhibits resistance to allosteric inhibition by STLC.

Indorato R, DeBonis S, Garcia-Saez I, Skoufias D Front Oncol. 2022; 12:965455.

PMID: 36313676 PMC: 9597087. DOI: 10.3389/fonc.2022.965455.

Acentriolar spindle assembly in mammalian female meiosis and the consequences of its perturbations on human reproduction†.

Blengini C, Schindler K Biol Reprod. 2021; 106(2):253-263.

PMID: 34791041 PMC: 8862719. DOI: 10.1093/biolre/ioab210.

Mechanisms by Which Kinesin-5 Motors Perform Their Multiple Intracellular Functions.

Pandey H, Popov M, Goldstein-Levitin A, Gheber L Int J Mol Sci. 2021; 22(12).

PMID: 34203964 PMC: 8232732. DOI: 10.3390/ijms22126420.

Monastrol derivatives: and cytotoxicity assessments.

Bidram Z, Sirous H, Khodarahmi G, Hassanzadeh F, Dana N, Hariri A Res Pharm Sci. 2020; 15(3):249-262.

PMID: 33088325 PMC: 7540817. DOI: 10.4103/1735-5362.288427.

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